Haematologic malignancies commonly arise from the bone marrow lesion, yet there are currently no effective targeted therapies against tumour cells in this location. Here we constructed a bone-marrow-targeting nanosystem, CSF@E-Hn, which is based on haematopoietic-stem-cell-derived nanovesicles adorned with gripper ligands (aPD-L1 and aNKG2D) and encapsulated with colony-stimulating factor (CSF) for the treatment of haematologic malignancies. CSF@E-Hn targets the bone marrow and, thanks to the gripper ligands, pulls together tumour cells and natural killer cells, activating the latter for specific tumour cell targeting and elimination. The therapeutic efficacy was validated in mice bearing acute myeloid leukaemia and multiple myeloma. The comprehensive assessment of the post-treatment bone marrow microenvironment revealed that the integration of CSF into a bone-marrow-targeted nanosystem promoted haematopoietic stem cell differentiation, boosted memory T cell generation and maintained bone homoeostasis, with long-term prevention of relapse. Our nanosystem represents a promising strategy for the treatment of haematologic malignancies.

血液系统恶性肿瘤通常起源于骨髓病变，但目前没有针对该部位肿瘤细胞的有效靶向治疗。在这里，我们构建了一个靶向骨髓的纳米系统 CSF@E-Hn，它基于造血干细胞衍生的纳米囊泡，装饰有夹持配体 （aPD-L1 和 aNKG2D） 并用集落刺激因子 （CSF） 封装，用于治疗血液系统恶性肿瘤。CSF@E-Hn 靶向骨髓，并且由于夹持配体，将肿瘤细胞和自然杀伤细胞拉到一起，激活后者以进行特异性肿瘤细胞靶向和消除。治疗效果在患有急性髓系白血病和多发性骨髓瘤的小鼠中得到验证。对治疗后骨髓微环境的综合评估显示，将 CSF 整合到骨髓靶向纳米系统中促进了造血干细胞分化，促进了记忆 T 细胞的生成并维持了骨均质稳定，并长期预防复发。我们的纳米系统代表了治疗血液系统恶性肿瘤的一种有前途的策略。